The invertebral disc (IVD) is the largest predominantly avascular, aneural and alymphatic structure in the human body. The disc is critical for the normal function of the spinal column since it provides flexibility and mechanical stability during axial compression, flexion and extension. The IVD is composed of several specialised connective tissues: (i) the hyaline cartilage of the cartilaginous end plates (CEPs) which cover the surface of the vertebral bones (bodies) which are positioned above and below the disc; (ii) the fibrocartilagenous annulus fibrosus (AF) which encapsulates the nucleus pulposus (NP); and (iii) the central gelatinous nucleus pulposus (NP) which although it contains cartilage like cells is not a hyaline cartilage. A transitional zone (TZ) has also been identified which, as its name implies, is located between the AF and NP. The fibrocartilagenous AF is composed of concentric collagenous layers (lamellae) that are connected to the bony-rim of the vertebral bodies.
Proteoglycans (PGs) and types I, II, III, V, VI, IX, X, XI collagens are the major matrix components of all these disc tissues but their relative abundance and distribution is dependent on their anatomical locations. PGs, which have a high affinity for water molecules, are most abundant in the NP of “healthy discs”. The water imbibed by the PGs generates a hydrostatic pressure within the NP that “inflates” the encapsulating fibrocartilagenous AF. It is the combination of these specialised connective tissues with their individual physiochemical properties that contributes to the hydrodynamic and viscoelastic properties of the IVD that are essential for the normal biomechanical function of the spinal column.
The IVD undergoes profound matrix changes during ageing and degeneration. Studies of human cadaveric and disc specimens obtained at the time of spinal surgery have shown that discs from individuals in the middle to older age groups generally have a wide range of lesions (1, 2).
Three major types of disc lesions have been identified from these specimens: (i) the rim lesion, a transverse defect close to the attachment of the AF to the bone of the vertebral body rim; (ii) the concentric (circumferential) tear, where the annular lamellae separate from each other; and (iii) the radiating tear which results from the propagation of clefts initiating within the NP (1, 2, 3). Rim-lesions are of particular interest since they appear more commonly in adolescence and early adult life within the anterior region of the AF close to its insertion into the bone of the vertebral rim suggesting that they may be mechanically mediated. Their presence suggests early failure of the AF and is the primary cause of disc degeneration but studies on cadaveric specimens also indicate that other pathological features (concentric tears, cystic annular degeneration, dehydration of the NP, vertebral rim syndesmophytes and osteoarthritis of the posterior intervertebral joints) are also invariably present to some degree (1, 2). Although the temporal history of these respective disc lesions still remains the subject of debate it is generally agreed that loss of PGs and its associated water from the NP is an early etiological determinant of disc degeneration (4).
As already discussed the disc functions as a flexible hydro elastic cushion, largely mediated by the imbibition of water molecules within the NP. A decline in water content and thus swelling pressure of the NP would lead to the imposition of supraphysiological mechanical stresses on the AF resulting in localised failure.
Medical problems associated with back and neck-pain arising from disc degeneration are experienced by 90% of the population some time during their lives (5, 6). In man, back or neck pain of sufficient severity to warrant medical intervention increases in incidence in the third and fourth decades of life, peaks in the fifties and declines thereafter (5).
In the USA, back pain is the second most common reason for visit to a physician and medical conditions related to back and neck pain account for more hospitalisations than any other musculoskeletal disorder. Back pain is the primary cause of lost working hours. For example, in the United Kingdom it has been estimated that more than 11 million working days are lost annually from this complaint. Moreover, as the longevity of the population increases over the next few decades, back and neck pain problems are expected to increase accordingly.
Despite the high incidence and economic burden of neck and back pain in modern societies, the causes are still poorly understood. There is however general agreement that degeneration and/or failure if the IVD is the primary cause of pain, either directly from the nerves present in the outer AF or from the adjacent spinal structures that become mechanically compromised by the loss of disc hydroelastic function (7, 8, 9, 10). Disc disease is responsible for 23-40% of all cases of low back pain (11, 12). The outer AF is innervated and nerve fibres may extend as deeply as its inner third, thus any pathological changes to the outer AF may invoke pain (13, 14, 15).
The existing paradigm for treating back or neck pain of discal origin is empirical, directed either toward life-style changes or use of anti-inflammatory/analgesic drugs to minimise the symptomatology or to surgical intervention that may require resection of the degenerate tissues or spinal arthrodesis to restrict movement. Notwithstanding the widespread use of spinal fusion for the relief of neck or low back pain it is known that this is not a benign procedure since the mechanical stress imposed on adjacent discs by the introduction of the rigid segment across the disc space accelerates degenerate changes in adjacent discs which may become symptomatic at a later stage (16). Clearly alternative methods of treatment are required.
Intra-discal administration of the protein, osteogenic protein-1 (OP-1) (Bone morphogenetic protein-7), has been reported to stimulate disc matrix repair following experimentally produced degeneration. Disc degeneration was produced in rabbits by prior injection of the depolymerising enzyme chondroitinase ABC into the disc NP—the procedure being known as chemonucleolysis (17). Both NP and AF cells were found to be far more efficient at re-establishing a functional matrix after chemonucleolysis. Disc cells embedded in a normal dense extracellular matrix were found to be largely un-responsive to the stimulatory effects of OP-1 on PG synthesis (17).
Studies examining potential cellular therapies to achieve repair of degenerate canine and human IVDs using autologous chondrocytes have been reported (18, 19). The cells used were the chondrocytes harvested from healthy NP of the same species and subsequently re-implanted into the defect disc. The disadvantage of this approach is that the cells used for this purpose would need to be harvested from adjacent healthy discs or from other donors of the same species. Violation of the AF is required to obtain such cells and this process not only damages AF structure but also the removal of viable cells from the NP would accelerate degenerative changes in this tissue. Clearly this procedure would have limited human application.